Novel carbamoyloxy arylalkan arylpiperazine compound, pharmaceutical compositions comprising the compound and method for treating pain, anxiety and depression by administering the compound

ABSTRACT

There is provided a novel carbamoyloxy arylalkanoyl arylpiperazine derivative compound having abundant racemic or enantiomeric characteristics, represented by the Formula 1, and pharmaceutically available salts or hydrates thereof. Also, there are provided a pharmaceutical composition for treating pain, anxiety or depression including an effective amount of the compound, and a method for treating pain, anxiety or depression in mammals by administering an effective amount of the compound to the mammals in need of treatment thereof.

TECHNICAL FIELD

The present invention relates to novel carbamoyloxy arylalkanoylarylpiperazine compound, a pharmaceutical compositions comprising thecompound and a method for treating pains including acute pain, chronicpain, neurthic pain, post-surgery neuropathic pain, diabetic neuropathicpain, postherpetic neuralgia, inflammatory pain, joint pain, migraineheadache and the like, anxiety and depression in mammals byadministering the compound to the mammals in need of treatment thereof.

BACKGROUND ART

Up to now, arylpiperazine compounds were proven to be effective to avariety of indications in the field of central nervous system. Inparticular, U.S. Pat. No. 3,002,976 reported that the followingthiophene-engrafted arylpiperazine compound has a pharmacological effectto treat depression. In this formula, R represents hydrogen, methylgroup or halogen.

Also, it has been known that effects of buspirone and its structurallyrelated compounds on the treatment of anxiety is due to their selectiveactivities in serotonin (5-hydroxytryptamine: 5HT) sub-type receptorrepresented by a receptor 5-HT1A. In particular, U.S. Pat. No. 4,988,814discloses piperazine derivatives showing affinity to the 5-HT1A receptorcharacterized as therapeutic agents to treat depression and anxiety.

wherein, R′ is alkyl having carbon atoms of 1 to 6; R² and R′ are eachindependently alkyl having carbon atoms of 1 to 6, or R² and R³ aretaken together to form polymethylene having carbon atoms of 2 to 12 orto form a 5-norbornen-2-yl residue with carbon atoms bount to theradicals R² and R³; X is selected from the group consisting of —CO₂—,—OCO—, —OCO₂—N(R⁷)CO—, —NHNHCO—, —ON(R⁷)CO—, —CON(R⁷)—, —N(R⁷)CO—,—OCON(R⁷)— and —N(R⁷)CON(R⁸) (wherein, R⁷ and R⁸ are each independentlyis selected from the group consisting of hydrogen; alkyl having carbonatoms of 1 to 6; phenyl; benzyl; and phenyl or benzyl substituted byhalo, alkyl having carbon atoms of 1 to 6, alkoxy having carbon atoms of1 to 6, cyano, nitro or perhalomethyl); R⁴ is hydrogen or alkyl havingcarbon atoms of 1 to 6; R⁵ is selected from the group consisting ofhydrogen; alkyl having carbon atoms of 1 to 8; hydroxyalkyl havingcarbon atoms of 1 to 3; phenyl; benzyl; and phenyl or benzyl substitutedby hydroxy, halo, alkyl having carbon atoms of 1 to 6, alkoxy havingcarbon atoms of 1 to 6, trifluoromethyl, nitro, cyano, carbalkoxy havingcarbon atoms of 2 to 7, carboxamido, amino, alkylamino having carbonatoms of 1 to 6 or dialkylamino having carbon atoms of 2 to 12; R⁶ isphenyl, benzyl, 2-, 3- or 4-pyridinyl, 2-pyrimidinyl or 2-pyrazinyl thatmay be substituted by at least one substituents selected from the groupconsisting of hydroxy, halo, alkyl having carbon atoms of 1 to 6, alkoxyhaving carbon atoms of 1 to 6, trifluoromethyl, nitro, cyano, carbalkoxyhaving carbon atoms of 2 to 7, carboxamido, amino, alkylamino havingcarbon atoms of 1 to 6, and dialkylamino having carbon atoms of 2 to 12;n is one integer selected from the group consisting of 0, 1, 2, 3, 4 and5, provided that R⁶ is not 2-pyrindinyl when X is —CON(R⁷)— (wherein, R⁷is alkyl), and R⁶ is not 3,5-di(trifluoromethyl)phenyl when X is CO, R′,R² and R³ are methyl and n is 1.

The present inventors have confirmed that an arylpiperazine structure iscorrelated with an effect to treat pains as well as anxiety anddepression, conducted comprehensive researches on the arylpiperazinestructure, and found that novel carbamoyloxy arylalkanoyl arylpiperazinecompounds have a medical effect in various pain-induced animal models.In particular, the present inventors have found that the novelcarbamoyloxy arylalkanoyl arylpiperazine compounds show theirtherapeutic effects to treat a wide scope of pains including acute pain,chronic pain, neuropathic pain, post-surgery neuropathic pain, diabeticpain, postherpetic neuralgia, inflammatory pain, joint pain, migraineheadache and the like, anxiety and depression. Therefore, the presentinvention was completed on the basis of the above-mentioned facts.

DISCLOSURE OF INVENTION Technical Problem

An aspect of the present invention provides a novel carbamoyloxyarylalkanoyl arylpiperazine derivative compound and pharmaceuticallyavailable salts or hydrates thereof.

Another aspect of the present invention provides a pharmaceuticalcomposition for treating pain, anxiety or depression including aneffective amount of the compound.

Still another aspect of the present invention provides a method fortreating pain, anxiety or depression in mammals by administering aneffective amount of the compound to the mammals in need of treatmentthereof.

Technical Solution

According to an aspect of the present invention, there is provided anovel carbamoyloxy arylalkanoyl arylpiperazine derivative compoundhaving abundant racemic or enantiomeric characteristics, represented bythe following Formula 1, and pharmaceutically available salts orhydrates thereof:

wherein,

may selectively form a cyclic ring;

R₁ and R₂ are each independently selected from the group consisting ofhydrogen, straight or branched alkyl having carbon atoms of 1 to 6, andphenethyl, or R₁ and R₂ may be taken together to form a 5-membered or6-membered heterocyclic ring or R₁ or R₂ may be taken together with Ar₁to form a bicyclic ring;

Ar₁ is selected from the group consisting of furanyl, thionyl,methylenedioxyphenyl, and phenyl that may be substituted by at least oneidentical or different substituent selected from the group consisting ofhydrogen, straight or branched alkyl having carbon atoms of 1 to 6,halogen such as F, Cl and Br, straight or branched alkoxy having carbonatoms of 1 to 6, nitro, and trifluoromethyl;

Z is hydrogen or fluorine, or may be taken together with Ar₁ to form abicyclic ring;

Ar₂ is selected from the group consisting of phenyl,methylenedioxyphenyl, pyridine, pyrimidine, naphthyl, bis(fluorophenyl)methyl and quinoxaline, all of which may be substituted by atleast one identical or different substituent selected from the groupconsisting of hydrogen, straight or branched alkyl having carbon atomsof 1 to 6, hydroxy, halogen, straight or branched alkoxy having carbonatoms of 1 to 6, nitro, acetyl, t-butylacetyl, trifluoromethyl, amino,and acetate;

n is integer of 1 or 2; and

m is integer ranging from 0 to 2.

According to another aspect of the present invention, there is provideda pharmaceutical composition for treating pain, anxiety or depressionincluding an effective amount of the compound having abundant racemic orenantiomeric characteristics.

According to still another aspect of the present invention, there isprovided a method for treating pain, anxiety or depression in mammals byadministering to the mammals in need of treatment thereof an effectiveamount of the compound having abundant racemic or enantiomericcharacteristics.

ADVANTAGEOUS EFFECTS

As described above, the novel carbamoyloxy arylalkanoyl arylpiperazinederivative compound, and salts and hydrates thereof according to thepresent invention may be effectively used as a therapeutic agent fortreating pains including acute pain, chronic pain, neuropathic pain,post-surgery neuropathic pain, diabetic neuropathic pain, postherpeticneuralgia, inflammatory pain, joint pain and migraine headache and thelike, anxiety and depression.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail.

The present invention is related to a carbamoyloxy arylalkanoylarylpiperazine derivative compound having abundant racemic orenantiomeric characteristics, represented by the following Formula 1,and pharmaceutically available salts or hydrates thereof:

wherein,

may selectively form a cyclic ring;

R₁ and R₂ are each independently selected from the group consisting ofhydrogen, straight or branched alkyl having carbon atoms of 1 to 6, andphenethyl, or R₁ and R₂ may be taken together to form a 5-membered or6-membered heterocyclic ring or R₂ may be taken together with Ar₁ form abicyclic ring;

Ar₁ is selected from the group consisting of furanyl, thionyl,methylenedioxyphenyl, and phenyl that may be substituted by at least oneidentical or different substituent selected from the group consisting ofhydrogen, straight or branched alkyl having carbon atoms of 1 to 6,halogen such as F, Cl and Br, straight or branched alkoxy having carbonatoms of 1 to 6, nitro, and trifluoromethyl;

Z is hydrogen or fluorine, or may be taken together with Ar₁ to form abicyclic ring;

Ar₂ is selected from the group consisting of phenyl,methylenedioxyphenyl, pyridine, pyrimidine, naphthyl, bis(fluorophenyl)methyl and quinoxaline, all of which may be substituted by atleast one identical or different substituent selected from the groupconsisting of hydrogen, straight or branched alkyl having carbon atomsof 1 to 6, hydroxy, halogen, straight or branched alkoxy having carbonatoms of 1 to 6, nitro, acetyl, t-butylacetyl, trifluoromethyl, amino,and acetate;

n is integer of 1 or 2; and

m is integer ranging from 0 to 2.

Also, the present invention is related to a compound represented by thefollowing Formula 2, and pharmaceutically available salts or hydratesthereof:

wherein, R₁, R₂, Z, Ar₂, n and m are defined as in the Formula 1; and

X₁ is at least one selected from the group consisting of hydrogen,straight or branched alkyl having carbon atoms of 1 to 6, halogens suchas F, Cl and Br, straight or branched alkoxy having carbon atoms of 1 to6, nitro, and trifluoromethyl,

provided that, when X is at least two selected from the groups, the twosubstituents may be identical to, or different from each other.

In addition, the present invention is related to a compound representedby the following Formula 3, and pharmaceutically available salts orhydrates thereof:

wherein, X₁, R₁, R₂, Z, Ar₂, n and m are defined as above; and

X₂ is at least one selected from the group consisting of hydrogen,straight or branched alkyl having carbon atoms of 1 to 6, hydroxy,halogen, straight or branched alkoxy having carbon atoms of 1 to 6,nitro, acetyl, t-butylacetyl, trifluoromethyl, amino, acetate, andacetate,

provided that, when X₂ is at least two selected from the groups, the twosubstituents may be identical to, or different from each other.

The compounds according to one exemplary embodiment of the presentinvention may be chemically synthesized as in the following Schemes 1and 2. However, they are described for the purpose of illustrationsonly, and the present invention is not particularly limited thereto.

In the following Schemes, HX represents acids that may formpharmaceutically available salts with a compound having basic nitrogenatoms. The acids includes, for example, hydrochloric acid, sulfuricacid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonicacid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinicacid, tartaric acid, lactic acid, gluconic acid, ascorbic acid, maleicacid, aspartic acid, benzenesulfonic acid, methanesulfonic acid,ethanesulfonic acid, hydroxyymethanesulfonic acid andhydroxyethanesulfonic acid, but the present invention is notparticularly limited thereto. Additional acids may refer to a literature[“Pharmaceutical Salts,” J. Pharm. 1977; 66(1): 1-19]. The preparationof the compound of the present invention is carried out in a reactionmedium that may be illustrated as an ether solvent (tetrahydrofuran,ethylether, propylether, isopropylether, and butylether), an alcoholsolvent (methanol, ethanol, and isopropyl alcohol), an ester solvent(ethyl acetate), a halogenated hydrocarbon solvent (dichloromethane,chloroform) and mixtures thereof.

Acetophenone substituted by X₁ as shown in the Scheme 1 and a compound(1-2) are refluxed in a toluene solvent to synthesize a compound (1-3).The compound (1-3) is reduced with sodium borohydride (NaBH₄) to obtainan alcohol intermediate (1-4), and the alcohol intermediate (1-4) isreacted with 1,1-carbonyldiimidazole (CDT), and then with various amines(NHR₁R₂) to obtain a compound (1-5). In the Scheme 1, HX represents acidthat may produce pharmaceutically available salts with basic amine.According to the Scheme 1, the compound (1-5) is dissolved in a reactionmedium such as an ether solvent (tetrahydrofuran, ethylether), an estersolvent (ethyl acetate), a halogenated hydrocarbon solvent(dichloromethane, chloroform), or the like, and corresponding HX isadded slowly to obtain a salt compound (1-6). In particular,hydrochloric acid and methanesulfonate salt are generally prepared, andtheir medicinal effects are measured. Also, the reaction product (1-5)or (1-6) prepared in the Scheme 1, is obtained all in the form ofracemic compound.

As shown in the Scheme 2, 3-hydroxy-3-phenylpropionic acid substitutedby X and a phenylpiperazine compound (2-2) are subject to a bindingreaction at the presence of1-ethyl-3-(3-dimethylaminopropypcarbodiimide/1-hydroxy benzotriazole(EDC/HOST) to synthesize an amide compound (2-3). The amide compound(2-3) is reacted with 1,1-carbonyldiimidazole (CDI), and then reactedwith various amines (NHR₁R₂) to obtain a compound (2-4) and its salt(2-5).

The stereochemistry of the reaction product (2-5) depends only on thestarting material (2-1); that is, a reaction product having an(S)-enantiomer only is obtained from the starting material (2-1) havingan (S)-enantiomer, and a reaction product having a (R)-enantiomer onlyis obtained from the starting material (2-1) having a (R)-enantiomer.

According to the present invention, there is provided a pharmaceuticalcomposition including an effective amount of the compound to treat pain,anxiety or depression. Here, the pharmaceutical composition includes, asan active component, at least one compound among the compounds as listedin this application, and the composition according to the presentinvention may include any combination of the compounds according to thepresent invention.

The pharmaceutical composition of present invention may be specificallyformulated so that it can be administered via any form, such as suitableroutes of administration. Here, the suitable routes of administrationmay, for example, include oral, rectal, nasal, pulmonary, local,percutaneous, intracisternal, intraperitoneal, vaginal, and parenteral(including subcutaneous, intramuscular, intrathecal, intravenous andtransdermal routes) routes. The pharmaceutical composition of presentinvention is preferably administered via the oral route. The preferredroutes of administration will, of course, be varied depending on avariety of factors, including the general conditions and age of thesubject being treated, the severity of the conditions being treated, andthe selected active components, etc.

Pharmaceutical preparations formulated according to the presentinvention may be administered orally in any form of administration, suchas suitable forms of a tablet, a capsule, a powder, a granule, a pellet,a troche, a dragee, a pill or lozenge, a solution or suspension in anaqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquidemulsion, an elixir, a syrup, etc., or be administered parenterally inthe form of injections. Other pharmaceutical compositions that may beadministered parenterally include a dispersion, a suspension and anemulsion, as well as sterile powders included in a sterile injectionsolution or dispersion before their use. It is considered that a depotinjection formulation is also included within the scope of the presentinvention. Other suitable forms of administration include a suppository,a spray, an ointment, a cream, a gelatin, an inhalant, a skin patch,etc. The composition according to the present invention may beformulated according to various methods known in the art. Also,pharmaceutically available carrier, diluent, excipient or otheradditives, which are used in general in the art, may be used herein.

The carrier that which generally used in formulations includes, but isnot particularly limited to, lactose, dextrose, sucrose, sorbitol,mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin,calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate,propyl hydroxy benzoate, talc, magnesium stearate, mineral oil, etc. Thecomposition of the present invention may further includes apreservative, a stability-improving compound, aviscosity-improving/regulating compound, a solubility-improvingcompound, a sweetener, a dye, a taste-enhancing compound, anosmosis-inducing salt, a buffer, an antioxidant, etc.

Where the above-mentioned compounds show a desired effect to treat pain,anxiety or depression, the compounds may be used in the form ofsolvates, esters, stereoisomers, etc. including free compounds,pharmaceutically available salts and hydrates. Also, the above-mentionedcompounds are all included in the scope of the present invention.

According to the present invention, the pharmaceutically available saltsmay include pharmaceutically available acid addition salts. Thepharmaceutically available acid addition salts may be obtained frominorganic acids such as hydrochloric acid, nitric acid, phosphoric acid,sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid andphosphorous acid; and non-toxic organic acids such as aliphatic mono anddicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate andalkandioate, aromatic acids, aliphatic and aromatic sulfonic acids; andthe like. Specific examples of the pharmaceutically available saltsincludes, but is not particularly limited to, sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride,bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate,acrylate, formate, isobutyrate, caprate, heptanoate, propionate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,phthalate, terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, p-hydroxybutyrate,glycolate, maleate, tartrate, methane sulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate and mandelate.Particularly, hydrochloric acid and methane sulfonate are preferred.

The present invention provides a method for treating pain, anxiety ordepression in mammals, characterized in that an effective amount of thecompound is administered to the mammals in need of treatment thereof.

The pain, which may be treated by the compound of the present invention,includes a wide range of pains such as acute pain, chronic pain,neuropathic pain, post-surgery neuropathic pain, diabetic neuropathicpain, postherpetic neuralgia, inflammatory pain, joint pain, migraineheadache and the like, anxiety and depression.

In general, the pharmaceutical composition of the present invention isadministered with an active component at a unit dose ranging fromapproximately 20 to 500 mg. The total daily dose may be generallyadministered at the amount ranging from approximately 10 to 7000 mg, andpreferably from 20 to 3500 mg of the active compound of the presentinvention. However, the active compound may also be administered at acertain amount out of the dose range under general investigation of theconditions of patients, and also in consideration of the activity ofagents to be administered. In this case, the optimum dose amount of suchagents in the particular conditions should be determined by routineexperimentations.

The compound of the present invention may be administered in single ormultiple daily doses, and the dose of the compound may be preferablydivided into one to four times per day. The compound of the presentinvention may be administered alone or in combination of apharmaceutically available carrier or an excipient. The pharmaceuticalcomposition according to the present invention may be formulated in apharmaceutically available carrier or a diluent, as well as in asupplement and an excipient that are widely known in the art. Forconvenience' sake, the formulations may be present in dosages suitablefor such administration by using the methods known in the field ofpharmacology.

MODE FOR THE INVENTION

Hereinafter, exemplary embodiments of the present invention will bedescribed in detail. However, it should be understood that thedescription proposed herein is just a preferable example for the purposeof illustrations only, not intended to limit the scope of the invention.

1. Synthesis of Carbamoyloxy Arylalkanoyl Arylpiperazine Compounds

Example 1 Carbamic acid3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

Ethyl benzoylacetate (2.887 mmol) and 4-fluorophenylpiperazine (2.887mmol) were dissolved in toluene, and refluxed for 24 hours. Theresulting reaction mixture was concentrated under a reduced pressure,and dissolved in methanol, and cooled to 0° C., and sodium borohydride(2.887 mmol) was then added dropwise to the resulting mixture. Theresulting mixture was stirred at a room temperature for 2 hours,concentrated under a reduced pressure, diluted with water, and thenextracted several times with ethyl acetate to obtain an organic phase.The resulting organic phase was dried over magnesium sulfate, filtered,and then concentrated under a reduced pressure. The resulting mixturewas purified with column chromatography (hexane:ethyl acetate=1:1) toobtain a compound. The prepared compound was dissolved intetrahydrofuran (10 mL), and 1,1′-carbodiimidazole (5 mmol) was added tothe resulting mixture. Then, the resulting mixture was stirred at a roomtemperature for 1 hour, and excessive ammonium hydroxide was added tothe reaction mixture. The resulting reaction mixture was stirred at aroom temperature for 1 hour. The reaction mixture was diluted withwater, and extracted several times with ethyl acetate to obtain anorganic phase. The prepared organic phase was dried over magnesiumsulfate, filtered, and then concentrated under a reduced pressure. Theresulting pellet was purified with column chromatography (ethyl acetate)to obtain a title compound.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.03 (m, 5H), 3.60 (m, 2H),3.76 (m, 2H), 4.73 (br, 2H), 6.16 (t, 1H), 6.95 (m, 4H), 7.38 (m, 5H)

Compounds of Examples 2 to 60 were prepared in the same manner as in theExample 1, except that the different starting materials were used in theExamples 2 to 60.

Example 2 Carbamic acid 3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 4-methoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 3.00 (m, 6H), 3.60 (m, 2H), 3.79 (m, 5H),4.82 (br, 2H), 6.18 (t, 1H), 6.88 (m, 4H), 7.38 (m, 5H).

Example 3 Carbamic acid3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,4-dichlorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.09 (m, 5H), 3.58 (m, 2H),3.74 (m, 2H), 4.81 (br, 2H), 6.14 (t, 1H), 6.73 (dd, 1H), 6.94 (d, 1H),7.40 (m, 6H)

Example 4 Carbamic acid 3-oxo-1-phenyl-3-(4-p-tolylpiperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 4-methylphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.30 (s, 3H), 2.82 (dd, 1H), 3.05 (m, 5H),3.60 (m, 2H), 3.77 (m, 2H), 4.77 (br, 2H), 6.15 (t, 1H), 6.84 (d, 2H),7.10 (d, 2H), 7.38 (m, 5H)

Example 5 Carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,4-dimethoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.04 (m, 5H), 3.61 (m, 2H),3.77 (m, 2H), 3.88 (d, 6H), 4.77 (br, 2H), 6.15 (t, 1H), 6.42 (d, 1H),6.57 (s, 1H), 6.82 (d, 1H), 7.41 (m, 5H)

Example 6 Carbamic acid1-(4-chloro-phenyl)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-chloro-benzoylacetate and3,4-dimethoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.01 (m, 5H), 3.61 (m, 2H),3.77 (m, 2H), 3.86 (d, 6H), 4.84 (br, 2H), 6.15 (t, 1H), 6.42 (d, 1H),6.57 (s, 1H), 6.82 (d, 1H), 7.35 (s, 4H)

Example 7 Carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-3-oxo-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-fluoro-benzoylacetate and3,4-dimethoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.01 (m, 5H), 3.60 (m, 2H),3.75 (m, 2H), 3.86 (d, 6H), 4.92 (br, 2H), 6.15 (t, 1H), 6.42 (d, 1H),6.56 (d, 1H), 6.80 (d, 1H), 7.04 (t, 2H), 7.38 (t, 2H)

Example 8 Carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-p-tolyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-methyl-benzoylacetate and3,4-dimethoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.35 (s, 3H), 2.82 (dd, 1H), 3.04 (m, 5H),3.62 (m, 2H), 3.77 (m, 2H), 3.88 (d, 6H), 4.67 (br, 2H), 6.11 (t, 1H),6.47 (dd, 1H), 6.58 (d, 1H), 6.81 (d, 1H), 7.18 (d, 2H), 7.32 (d, 2H)

Example 9 Carbamic acid3-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 2,4-dimethoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.89 (m, 6H), 3.59 (m, 2H), 3.82 (m, 8H),4.98 (br, 2H), 6.12 (t, 1H), 6.42 (dd, 1H), 6.49 (d, 1H), 6.79 (d, 1H),7.35 (m, 5H)

Example 10 Carbamic acid3-[4-(3,5-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,5-dichlorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.13 (m, 5H), 3.56 (m, 2H),3.75 (m, 2H), 4.76 (br, 2H), 6.14 (t, 1H), 6.73 (m, 2H), 6.86 (m, 1H),7.39 (m, 5H)

Example 11 Carbamic acid3-[4-(3,5-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,5-dimethoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.11 (m, 5H), 3.56 (m, 2H),3.80 (m, 8H), 4.79 (br, 2H), 6.08 (m, 4H), 7.39 (m, 5H)

Example 12 Carbamic acid3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 2,3-dichlorophenylpiperazine,

¹H NMR (200 MHz, CDCl3) d: 2.96 (m, 6H), 3.62 (m, 2H), 3.80 (m, 2H),4.73 (br, 2H), 6.16 (t, 1H), 6.88 (dd, 1H), 7.31 (m, 7H)

Example 13 Carbamic acid3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 2,4-difluorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.95 (m, 6H), 3.61 (m, 2H), 3.80 (m, 2H),4.69 (br, 2H), 6.15 (t, 1H), 6.82 (m, 3H), 7.35 (m, 5H)

Example 14 Carbamic acid3-(4-benzo[1,3]dioxol-5-yl-piperazin-1-yl)-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and3,4-methylenedioxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.98 (m, 6H), 3.59 (m, 2H), 3.76 (m, 2H),4.71 (br, 2H), 5.94 (s, 2H), 6.15 (t, 1H), 6.36 (dd, 1H), 6.55 (s, 1H),6.74 (d, 1H), 3.40 (m, 5H)

Example 15 Carbamic acid1-(4-methoxy-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-methoxy-benzoyl acetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.11 (m, 5H), 3.60 (m, 2H),3.74 (m, 2H), 3.78 (s, 3H), 5.01 (br, 2H), 6.08 (t, 1H), 6.91 (m, 5H),7.33 (m, 4H)

Example 16 Carbamic acid1-(4-chloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-chloro-benzoylacetate and phenylpiperazine,

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.14 (m, 5H), 3.60 (m, 2H),3.74 (m, 2H), 4.81 (br, 2H), 6.12 (t, 1H), 6.94 (m, 3H), 7.33 (m, 6H)

Example 17 Carbamic acid3-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 4-tert-butylphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 1.32 (s, 9H), 2.82 (dd, 1H), 3.08 (m, 5H),3.60 (m, 2H), 3.76 (m, 2H), 4.68 (br, 2H), 6.18 (t, 1H), 6.94 (m, 2H),7.35 (m, 7H)

Example 18 Carbamic acid3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 4-hydroxyphenylpiperazine.

¹H NMR (200 MHz, DMSO) d: 2.82 (m, 6H), 3.56 (m, 4H), 5.93 (t, 1H), 6.51(br, 2H), 6.67 (d, 2H), 6.78 (d, 2H), 7.37 (m, 5H), 8.88 (s, 1H)

Example 19 Dimethyl carbamic acid3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

Ethyl benzoylacetate (2 mmol) and 4-methoxyphenylpiperazine (2 mmol)were dissolved in toluene, and refluxed for 24 hours. The resultingmixture was concentrated under a reduced pressure to obtain a crudecompound, and the crude compound was dissolved in methanol, and cooledto 0° C. Then, sodium borohydride (2 mmol) was added dropwise to theresulting mixture. The mixture was stirred at a room temperature for 2hours, concentrated under a reduced pressure, diluted with water, andthen extracted several times with ethyl acetate to obtain an organicphase. The prepared organic phase was dried over magnesium sulfate,filtered, and then concentrated under a reduced pressure. The resultingpellet was purified with column chromatography (hexane:ethylacetate=1:1) to obtain a compound. The prepared compound was dissolvedin tetrahydrofuran (8 mL), and 1,1′-carbodiimidazole (4 mmol) was addedto the resulting mixture. Then, the resulting mixture was stirred at aroom temperature for 1 hour, and excessive dimethylamine was added tothe reaction mixture. The resulting reaction mixture was stirred at aroom temperature for 1 hour. The reaction mixture was diluted withwater, and extracted several times with ethyl acetate to obtain anorganic phase. The prepared organic phase was dried over magnesiumsulfate, filtered, and then concentrated under a reduced pressure. Theresulting pellet was purified with column chromatography (ethyl acetate)to obtain a title compound.

¹H NMR (200 MHz, CDCl3) d: 2.95 (m, 12H), 3.60 (m, 2H), 3.74 (m, 2H),3.78 (s, 3H), 6.18 (t, 1H), 6.87 (m, 4H), 7.39 (m, 5H)

Example 20 Carbamic acid3-[4-(3,4-dimethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,4-dimethylphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.21 (s, 3H), 2.26 (s, 3H), 2.83 (dd, 1H),3.07 (m, 5H), 3.59 (m, 2H), 3.75 (m, 2H), 4.72 (br, 2H), 6.18 (t, 1H),6.68 (d, 1H), 6.74 (s, 1H), 7.05 (d, 1H), 7.38 (m, 5H)

Example 21 Carbamic acid3-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-oxo-1-phenyl-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and4,4′-difluorobisphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.30 (m, 4H), 2.75 (dd, 1H), 2.97 (dd, 1H),3.44 (m, 2H), 3.59 (m, 2H), 4.21 (s, 1H), 4.99 (br, 2H), 6.07 (t, 1H),6.99 (t, 4H), 7.33 (m, 9H)

Example 22 Carbamic acid3-oxo-1-phenyl-3-(4-quinoxalin-2-yl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 2-piperazin-1-yl-quinoxaline.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.10 (dd, 1H), 3.77 (m, 8H),4.71 (br, 2H), 6.15 (t, 1H), 7.42 (m, 6H), 7.71 (m, 2H), 7.94 (d, 1H),8.59 (s, 1H)

Example 23 Acetic acid 4-[4-(3-carbamoyloxy-3-phenyl-propionyl)-piperazin-1-yl]-phenyl ester

The compound ‘carbamic acid3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester (2mmol)’ prepared in Example 18 was dissolved in tetrahydrofuran 25 mL),and triethylamine (2.4 mmol) and acetylchloride (2.4 mmol) were added tothe mixture. The resulting mixture was stirred at a room temperature for5 hours. Then, the reaction mixture was diluted with water, andextracted several times with ethyl acetate to obtain an organic phase.The prepared organic phase was dried over magnesium sulfate, andconcentrated under a reduced pressure. The resulting pellet was purifiedwith column chromatography (hexane:ethyl acetate=1:1) to obtain a titlecompound.

¹H NMR (200 MHz, CDCl3) d: 2.28 (s, 3H), 2.80 (dd, 1H), 3.04 (m, 5H),3.58 (m, 2H), 3.72 (m, 2H), 4.95 (br, 2H), 6.12 (t, 1H), 6.87 (d, 2H),7.00 (d, 2H), 7.38 (m, 5H)

Example 24 Carbamic acid 3-oxo-1-phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 2-piperazin-1-yl-pyridine.

¹H NMR (200 MHz, CDCl3) d: 2.83 (dd, 1H), 3.10 (dd, 1H), 3.50 (6, 2H),3.72 (m, 2H), 4.76 (br, 2H), 6.16 (t, 1H), 6.67 (m, 2H), 7.41 (m, 6H),8.20 (m, 1H)

Example 25 Carbamic acid3-oxo-1-phenyl-3-(4-pyrimidin-2-yl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 2-piperazin-1-yl-pyrimidine.

¹H NMR (200 MHz, CDCl3) d: 2.84 (dd, 1H), 3.09 (dd, 1H), 3.51 (m, 2H),3.76 (m, 6H), 4.73 (br, 2H), 6.16 (t, 1H), 6.55 (t, 1H), 7.41 (m, 5H),8.33 (d, 2H)

Example 26 Carbamic acid 3-[4-(3,5-dichloropyridin-2-yl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and1-(3,5-dichloro-pyridine-2-yl)piperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.09 (dd, 1H), 3.28 (m, 4H),3.60 (m, 2H), 3.75 (m, 2H), 4.89 (br, 2H), 6.13 (t, 1H), 7.39 (m, 5H),7.63 (s, 1H), 8.13 (s, 1H)

Example 27 Carbamic acid3-[4-(4-chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and3-chloro-4-trifluoromethylphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.86 (dd, 1H), 3.11 (m, 5H), 3.60 (m, 2H),3.74 (m, 2H), 4.75 (br, 2H), 6.16 (t, 1H), 6.96 (dd, 1H), 7.15 (d, 1H),7.40 (m, 6H)

Example 28 Carbamic acid3-oxo-1-phenyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and4-trifluoromethylphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.24 (m, 5H), 3.62 (m, 2H),3.78 (m, 2H), 4.65 (br, 2H), 6.18 (t, 1H), 6.92 (d, 2H), 7.41 (m, 5H),7.52 (d, 2H)

Example 29 Carbamic acid 3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-3-oxo1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 2-fluorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.84 (dd, 1H), 3.04 (m, 5H), 3.62 (m, 2H),3.78 (m, 2H), 4.76 (br, 2H), 6.16 (t, 1H), 7.04 (m, 4H), 7.39 (m, 5H)

Example 30 Carbamic acid3-[4-(3-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3-fluorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.84 (dd, 1H), 3.13 (m, 5H), 3.59 (m, 2H),3.77 (m, 2H), 4.78 (br, 2H), 6.14 (t, 1H), 6.62 (m, 3H), 7.21 (m, 1H),7.41 (m, 5H)

Example 31 Carbamic acid3-oxo-3-(4-phenyl-piperazin-1-yl)-1-(4-trifluoromethyl-phenyl)-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-trifluoromethyl-benzoylacetate andphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.84 (m, 1H), 3.13 (m, 5H), 3.62 (m, 2H),3.78 (m, 2H), 4.92 (br, 2H), 6.22 (t, 1H), 6.92 (m, 3H), 7.31 (m, 2H),7.63 (m, 4H).

Example 32 Carbamic acid3-oxo-3-(4-phenyl-piperazin-1-yl)-1-p-tolyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-methyl-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.11 (m, 5H), 3.62 (m, 2H),3.77 (m, 2H), 4.71 (br, 2H), 6.12 (t, 1H), 6.93 (m, 3H), 7.30 (m, 6H)

Example 33 Carbamic acid3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,4-difluoro phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.03 (m, 5H), 3.59 (m, 2H),3.76 (m, 2H), 4.76 (br, 2H), 6.14 (t, 1H), 6.68 (m, 2H), 7.05 (q, 1H),7.40 (m, 5H)

Example 34 Carbamic acid1-(4-nitro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-nitro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.15 (m, 5H), 3.59 (m, 2H),3.76 (m, 2H), 4.93 (br, 2H), 6.14 (t, 1H), 6.91 (m, 3H), 7.28 (m, 2H),7.60 (d, 2H), 8.22 (d, 2H)

Example 35 Carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-(4-trifluoromethyl-phenyl)-propylester; hydrochloride

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-trifluoromethyl-benzoylacetate and 3,4-dimethoxyphenylpiperazine. The prepared title compound was dissolved indichloromethane, and a saturated HCl/ether solution was added to theresulting mixture to obtain hydrochloride of the title compound.

¹H NMR (200 MHz, DMSO) d: 2.90 (dd, 1H), 3.12 (dd, 1H), 3.34 (m, 4H),3.75 (s, 3H), 3.78 (s, 3H), 3.85 (m, 4H), 6.00 (m, 1H), 6.60 (br, 2H),7.01 (m, 2H), 7.20 (m, 1H), 7.60 (d, 2H), 7.75 (d, 2H)

Example 36 Carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-1-(4-nitro-phenyl)-3-oxo-propylester; hydrochloride

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-4-nitro-benzoylacetate and 3,4-dimethoxyphenylpiperazine. The prepared title compound was dissolved indichloromethane, and a saturated HCl/ether solution was added to theresulting mixture to obtain hydrochloride of the title compound.

¹H NMR (200 MHz, DMSO) d: 2.96 (dd, 1H), 3.16 (dd, 1H), 3.42 (m, 4H),3.76 (s, 3H) 3.78 (s, 3H), 3.92 (m, 4H), 6.05 (m, 1H), 6.64 (br, 2H),7.02 (m, 1H), 7.24 (m, 2H), 7.65 (d, 2H), 8.24 (d, 2H)

Example 37 Carbamic acid3-[4-(3,4-dichloro-benzyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,4-dichloro benzyl piperazine.

¹H NMR (200 MHz, CDCl3) d: 2.37 (m, 4H), 2.77 (dd, 1H), 3.02 (dd, 1H),3.45 (m, 4H), 3.63 (m, 2H), 4.74 (br, 2H), 6.11 (t, 1H), 7.16 (dd, 1H),7.39 (m, 5H)

Example 38 Carbamic acid3-[4-(4-chloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 4-chloro phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.07 (m, 5H), 3.58 (m, 2H),3.74 (m, 2H), 4.81 (br, 2H), 6.13 (t, 1H), 6.84 (d, 2H), 7.38 (m, 7H)

Example 39 Carbamic acid3-{4-[2-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-3-oxo-1-phenyl-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl benzoylacetate and 3,4-dichlorophenethylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.50 (m, 6H), 2.76 (m, 3H), 3.03 (dd, 1H),3.46 (m, 2H), 3.64 (m, 2H), 4.70 (br, 2H), 6.13 (t, 1H), 7.04 (dd, 1H),7.38 (m, 7H)

Example 40 Carbamic acid 4-[4-(3,4-dichloro-phenyl)-piperazinyl]-4-oxo-1-phenyl-butyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of 4-oxo-4-phenyl-butyl ester and 3,4-dichlorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.26 (m, 2H), 2.40 (m, 2H), 3.14 (m, 4H),3.57 (m, 2H), 3.75 (m, 2H), 4.72 (br, 2H), 5.76 (t, 1H), 6.75 (dd, 1H),6.96 (d, 1H), 7.37 (m, 6H)

Example 41 Carbamic acid4-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-4-oxo-1-phenyl-butyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of 4-oxo-4-phenyl-butyl ester and3,4-dimethoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.22 (m, 2H), 2.38 (m, 2H), 3.03 (m, 4H),3.58 (m, 2H), 3.77 (m, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 4.91 (br, 2H),5.76 (t, 1H), 6.42 (dd, 1H), 6.58 (d, 1H), 6.80 (d, 1H), 7.35 (m, 5H)

Example 42 Carbamic acid1-(2-nitro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-2-nitro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.94-3.19 (m, 6H), 3.67 (m, 4H), 4.84 (br,2H), 6.57 (dd, 1H), 6.91 (m, 3H), 7.28 (m, 2H), 7.69 (m, 2H), 7.96 (d,1H)

Example 43 Carbamic acid1-(2-chloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-2-chloro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.93 (d, 2H), 3.63 (m, 4H), 3.84 (m, 4H),4.78 (br, 2H), 6.43 (t, 1H), 6.88 (m, 3H), 7.30 (m, 5H), 7.49 (d, 1H)

Example 44 Carbamic acid1-(2-methoxy-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-2-methoxy-ethyl benzoylacetate andphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.90 (m, 2H), 3.15 (m, 4H), 3.73 (m, 4H),3.86 (s, 3H), 4.76 (br, 2H), 6.40 (q, 1H), 6.93 (m, 4H), 7.27 (m, 4H),7.39 (d, 1H)

Example 45 Carbamic acid1-(3-trifluoro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3-trifluoromethyl-benzoylacetate andphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.77 (m, 1H), 3.12 (m, 5H), 3.76 (tri, 4H),4.74 (br, 2H), 6.19 (q, 1H), 6.91 (m, 3H), 7.28 (m, 2H), 7.60 (m, 4H)

Example 46 Carbamic acid1-(3-bromo-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3-bromo-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.76 (m, 1H), 3.14 (m, 5H), 3.66 (m, 4H),4.72 (br, 2H), 6.10 (q, 1H), 6.90 (m, 3H), 7.32 (m, 5H), 7.54 (s, 1H)

Example 47 Carbamic acid2,2-difluoro-3-oxo-1-phenyl-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of 3-carbamoyloxy-2,2-difluoro-3-phenyl-propionic ester andphenyl piperazine.

¹H NMR (200 MHz, CDCl3) d: 3.14 (m, 4H), 3.79 (d, 4H), 4.81 (br, 2H),6.35 (q, 1H), 6.91 (m, 3H), 7.26 (m, 7H)

Example 48 Carbamic acid1-(3,4-dimethoxy-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3,4-dimethoxy-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.78 (dd, 1H), 3.08 (m, 5H), 3.61 (m, 4H),3.84 (s, 3H), 3.89 (s, 3H), 4.70 (br, 2H), 6.06 (t, 1H), 6.88 (m, 5H),7.26 (m, 3H)

Example 49 Carbamicacid-1-furan-3-yl-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of 3-furan-3-yl-3-oxo-propionic acid ethyl ester andphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.80 (dd, 1H), 3.09 (m, 5H), 3.71 (m, 4H),4.67 (br, 2H), 6.15 (t, 1H), 6.4 (s, 1H), 6.93 (d, 3H), 7.38 (m, 4H)

Example 50 Carbamic acid1-(3-methyl-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3-methyl-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.34 (s, 3H), 2.79 (d, 1H), 3.08 (m, 5H),3.66 (m, 4H), 4.68 (hr, 2H), 6.08 (t, 1H), 6.89 (m, 3H), 7.10 (m, 1H),7.23 (m, 5H)

Example 51 Carbamic acid1-(3-chloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3-chloro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.77 (dd, 1H), 3.07 (m, 5H), 3.58 (m, 2H),3.75 (m, 2H 4.68 (br, 2H), 6.11 (q, 1H), 6.91 (m, 3H), 7.28 (m, 6H)

Example 52 Carbamicacid-2-(4-phenyl-piperazine-1-carbonyl)-4,2,3,4-tetrahydro-naphthalene-1-ylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of 1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acidethyl ester and phenyl piperazine.

¹H NMR (200 MHz, CDCl3) d: 1.99 (d, 1H), 2.35 (q, 1H), 0.80 (m, 1H),3.08 (m, 4H), 3.40 (m, 1H), 3.71 (m, 4H), 4.66 (br, 2H), 6.15 (s, 1H),6.92 (m, 3H), 7.25 (m, 4H), 7.41 (d, 1H)

Example 53 Carbamic acid1-(3,4-dichloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3,4-dichloro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.75 (dd, 1H), 3.05 (m, 5H), 3.66 (m, 4H),4.73 (br, 2H), 6.08 (t, 1H), 6.91 (m, 3H), 7.27 (m, 3H), 7.42 (m, 1H),7.49 (m, 1H)

Example 54 Carbamic acid1-(2,3,4,5-pentafluoro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-2,3,4,5,6-pentafluoro-benzoylacetate andphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 3.14 (m, 6H), 3.67 (m, 4H), 5.16 (br, 2H),6.37 (t, 1H), 6.92 (m, 3H), 7.26 (m, 2H)

Example 55 Carbamic acid1-(3,5-trifluoromethyl-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propylester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3,5-trifluoromethyl-benzoylacetate andphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.79 (dd, 1H), 3.12 (m, 5H), 3.67 (m, 4H),4.71 (br, 2H), 6.27 (t, 1H), 6.92 (m, 3H), 7.28 (m, 3H), 7.84 (m, 2H)

Example 56 Carbamic acid1-(2,4-dichloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-2,4-dichloro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.91 (m, 2H), 3.17 (m, 4H), 3.74 (m, 4H),4.76 (br, 2H), 6.38 (q, 1H), 6.92 (m, 3H), 7.31 (m, 3H), 7.44 (m, 2H)

Example 57 Carbamic acid1-(2,5-difluoro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-2,5-difluoro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.87 (dd, 1H), 3.03 (q, 1H), 3.16 (m, 4H),3.71 (m, 4H), 4.72 (br, 2H), 6.30 (q, 1H), 6.97 (m, 4H), 7.14 (m, 1H),7.28 (m, 3H)

Example 51 Carbamic acid1-(2,4-dimethyl-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-2,4-dimethyl-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) cl: 2.27 (s, 3H), 2.41 (s, 3H), 2.78 (dd, 1H),3.05 (m, 5H), 3.68 (m, 4H), 4.74 (br, 2H), 6.28 (t, 1H), 6.95 (m, 5H),7.26 (m, 3H)

Example 59 Carbamic acidmethylenedioxy-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3,4-methylenedioxy-benzoylacetate andphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.77 (dd, 1H), 3.09 (m, 5H), 3.67 (m, 4H),4.65 (br, 2H), 5.96 (s, 2H), 6.05 (t, 1H), 6.77 (m, 1H), 6.89 (m, 5H),7.28 (m, 2H)

Example 60 Carbamic acid1-(3,4-difluoro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester

A title compound was prepared in the same manner as in Example 1 exceptfor the use of ethyl-3,4-difluoro-benzoylacetate and phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.75 (dd, 1H), 3.06 (m, 5H), 3.66 (m, 4H),4.73 (br, 2H), 6.08 (t, 1H), 6.91 (m, 3H), 7.20 (m, 5H)

Example 61 (R)-carbamic acid3-[4-(4-chloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

(R)-3-hydroxy-3-phenylpropionic acid (1.0 g, 6.0 mmole) and 4-chlorophenylpiperazine (1.18 g, 6.0 mmole) were dissolved in 50 mL of solvent‘tetrahydrofuran at a room temperature, and EDC (1.24 g, 6.0 mmole) andHOBt (0.81 g, 6 mmole) were added dropwise to the mixture. Then, theresulting mixture was stirred at 25° C. for 5 hours. The mixture wasdistilled under a reduced pressure to remove excessive solvents, and thesolvent-free mixture was neutralized with 1 normal aqueous sodiumchloride solution (20 mL), and 25 mL of ethyl acetate was added to theresulting mixture to separate an organic phase. Then, the preparedorganic phase was further extracted twice with 15 mL of ethyl acetate.The organic phase was dried over anhydrous magnesium sulfate (2 g), andfiltered, and the resulting filtrate was concentrated under a reducedpressure, and separated and purified with column chromatography(hexane:ethyl acetate=1:1 to 1:10). The resulting reaction product(0.345 g, 1 mmol) was dissolved in tetrahydrofuran (15 mL), and1,1′-carbodiimidazole (0.325 g, 2 mmol) was then added to the reactionproduct, and the resulting reaction mixture was stirred at a roomtemperature for 1 hour. Then, excessive aqueous ammonium hydroxide wasadded to the reaction mixture, and resulting reaction mixture wasstirred at a room temperature for additional 2 hours. The reactionmixture was diluted with water, and extracted several times with ethylacetate to obtain an organic phase. The prepared organic phase was driedover magnesium sulfate, and concentrated under a reduced pressure. Theresulting pellet was purified with column chromatography (hexane:ethylacetate=1:1 to ethyl acetate) to obtain a title compound.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.07 (m, 5H), 3.58 (m, 2H),3.74 (m, 2H), 4.81 (br, 2H), 6.13 (t, 1H), 6.84 (d, 2H), 7.38 (m, 7H)

Title compounds of Examples 62 to 71 and 78 to 87 were prepared in thesame manner as in Example 61, except that the different startingmaterials were used in the Examples 62 to 71 and 78 to 87.

Example 62 (R)-carbamic acid3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and 4-fluorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.03 (m, 5H), 3.60 (m, 2H),3.76 (m, 2H), 4.73 (br, 2H), 6.16 (t, 1H), 6.95 (m, 4H), 7.38 (m, 5H)

Example 63 (R)-carbamic acid3-[4-(4-ethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and 4-ethoxyphenylpiperazine.

¹H NMR (500 MHz, CDCl3) d: 1.38 (t, 3H), 2.80 (dd, 1H), 3.00 (m, 5H),3.55 (m, 2H), 3.74 (m, 2H), 3.99 (q, 2H), 4.81 (br, 2H), 6.12 (t, 1H),6.84 (m, 4H), 7.33 (m, 5H)

Example 64 (S)-carbamic acid3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and3,4-difluoro phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.03 (m, 5H), 3.59 (m, 2H),3.76 (m, 2H), 4.76 (br, 2H), 6.14 (t, 1H), 6.68 (m, 2H), 7.05 (q, 1H),7.40 (m, 5H)

Example 65 (S)-carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and3,4-dimethoxy phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.04 (m, 5H), 3.61 (m, 2H),3.77 (m, 2H), 3.88 (d, 6H), 4.77 (br, 2H), 6.15 (t, 1H), 6.42 (d, 1H),6.57 (s, 1H), 6.82 (d, 1H), 7.41 (m, 5H)

Example 66 (S)-carbamic acid3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and3,4-dichloro phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.09 (m, 5H), 3.58 (m, 2H),3.74 (m, 2H), 4.81 (br, 2H), 6.14 (t, 1H), 6.73 (dd, 1H), 6.94 (d, 1H),7.40 (m, 6H)

Example 67 (R)-carbamic acid3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and3,4-difluoro phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.03 (m, 5H), 3.59 (m, 2H),3.76 (m, 2H), 4.76 (br, 2H), 6.14 (t, 1H), 6.68 (m, 2H), 7.05 (q, 1H),7.40 (m, 5H)

Example 68 (R)-carbamic acid3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and3,4-dichloro phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.09 (m, 5H), 3.58 (m, 2H),3.74 (m, 2H), 4.81 (br, 2H), 6.14 (t, 1H), 6.73 (dd, 1H), 6.94 (d, 1H),7.40 (m, 6H)

Example 69 (S)-carbamic acid3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and 4-methoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 3.00 (m, 6H), 3.60 (m, 2H), 3.79 (m, 5H),4.82 (br, 2H), 6.18 (t, 1H), 6.88 (m, 4H), 7.38 (m, 5H)

Example 70 (R)-carbamic acid3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and 4-methoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 3.00 (m, 6H), 3.60 (m, 2H), 3.79 (m, 5H),4.82 (br, 2H), 6.18 (t, 1H), 6.88 (m, 4H), 7.38 (m, 5H)

Example 71 (R)-carbamic acid 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and3,4-dimethoxy phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.04 (m, 5H), 3.61 (m, 2H),3.77 (m, 2H), 3.88 (d, 6H), 4.77 (br, 2H), 6.15 (t, 1H)

Example 72 Phenethyl-carbamic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propylester

(R)-3-hydroxy-3-phenylpropionic acid (1.0 g, 6.0 mmole) and3,4-dimethoxy phenyl piperazine (1.18 g, 6.0 mmole) were dissolved in 50mL of a solvent ‘tetrahydrofuran at a morn temperature, and EDC (1.24 g,6.0 mmole) and HOBt (0.81 g, 6 mmole) were added dropwise to themixture. Then, the resulting mixture was stirred at 25° C. for 5 hours.The mixture was distilled under a reduced pressure to remove excessivesolvents, and the solvent-free mixture was neutralized with 1 normalaqueous sodium chloride solution (20 mL), and 25 mL of ethyl acetate wasadded to the resulting mixture to separate an organic phase. Then, theprepared organic phase was further extracted twice with 15 mL of ethylacetate. The organic phase was dried over anhydrous magnesium sulfate (2g), and filtered, and the resulting filtrate was concentrated under areduced pressure, and separated and purified with column chromatography(hexane:ethyl acetate=1:1 to 1:10). The resulting reaction product(0.345 g, 1 mmol) was dissolved in tetrahydrofuran (15 mL), and1,1′-carbodiimidazole (0.325 g, 2 mmol) was then added to the reactionproduct, and the resulting reaction mixture was stirred at a roomtemperature for 1 hour. Then, excessive phenethylamine was added to thereaction mixture, and resulting reaction mixture was stirred at a roomtemperature for additional 2 hours. The reaction mixture was dilutedwith water, and extracted several times with ethyl acetate to obtain anorganic phase. The prepared organic phase was dried over magnesiumsulfate, and concentrated under a reduced pressure. The resulting pelletwas purified with column chromatography (hexane:ethyl acetate=1:1 toethyl acetate) to obtain a title compound.

¹H NMR (200 MHz, CDCl3) d: 2.76 (m, 4H), 2.89 (m, 4H), 3.37 (m, 2H),3.56 (m, 2H), 3.74 (m, 2H), 3.78 (s, 3H), 3.82 (s, 3H), 6.11 (t, 1H),6.78 (d, 2H), 7.13 (m, 2H), 7.18 (m, 1H), 7.20 (m, 4H), 7.35 (m, 5H)

Example 72 Piperidine-1-carboxylic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl propylester

A title compound was synthesized in the same manner as in Example 72,except that piperidine was used instead of phenethylamine.

¹H NMR (200 MHz, CDCl3) d: 2.80 (m, 1H), 2.89 (m, 1H), 2.97 (m, 3H),3.10 (m, 1H), 3.42 (m, 4H), 3.57 (m, 1H), 1.61 (m, 1H), 3.72 (m, 2H),3.81 (s, 3H), 3.84 (s, 3H), 6.10 (t, 1H), 6.41 (d, 1H), 6.53 (d, 1H),6.77 (d, 1H), 7.32 (m, 5H)

Example 74 Butyl-carbamic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propylester

A title compound was synthesized in the same manner as in Example 72,except that butylamine was used instead of phenethylamine.

¹H NMR (200 MHz, CDCl3) d: 1.31 (m, 3H), 1.44 (m, 2H), 2.83 (m, 1H),3.06 (m, 5H), 3.14 (m, 4H), 3.58 (m, 2H), 3.74 (m, 2H), 3.83 (s, 3H),3.86 (s, 3H), 4.91 (t, 1H), 6.09 (m, 1H), 6.41 (d, 1H), 6.55 (d, 1H),6.79 (d, 1H), 7.34 (m, 5H)

Example 75 4-methyl-piperazine-1-carboxylic acid-(R)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propylester

A title compound was synthesized in the same manner as in Example 72,except that 4-methylpiperazine was used instead of phenethylamine.

¹H NMR (200 MHz, CDCl3) d: 2.24 (m, 4H), 2.00 (s, 3H), 2.96 (m, 2H),3.05 (m, 3H), 3.09 (m, 1H), 3.51 (m, 6H), 3.68 (m, 1H), 3.72 (m, 1H),3.82 (s, 3H), 3.86 (s, 3H), 6.11 (t, 1H), 6.39 (d, 1H), 6.51 (d, 1H),6.77 (d, 1H), 7.24 (d, 1H), 7.32 (m, 4H)

Example 76 (R)-carbamic acid3-[4-(4-amino-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

(R)-3-hydroxy-3-phenylpropionic acid (3.0 mmole) and 4-nitrophenylpiperazine (3 mmole) were dissolved in 20 mL of tetrahydrofuran ata room temperature, and EDC (6.0 mmole,1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide) and HOBt (6 mmole,N-Hydroxybenzotriazole) were added dropwise to the mixture. Then, theresulting mixture was stirred at 25° C. for 5 hours. 20 mL of ethylacetate was added three times to the mixture to extract an organicphase, and the prepared organic phase was dried over anhydrous magnesiumsulfate (2 g), and filtered, and the resulting filtrate was concentratedunder a reduced pressure, and purified with column chromatography(hexane:ethyl acetate=1:1). The resulting reaction product (1 mmol) wasdissolved in methanol (20 mL), and subject to the reduction reaction atthe presence of a palladium on charcoal (Pd/C) for 5 hours. Theresulting reduction reaction product was concentrated under a reducedpressure to remove methanol, and extracted several times with ethylacetate to separate an organic phase. The prepared organic phase wasdried over anhydrous magnesium sulfate, and filtered, and the resultingfiltrate was concentrated under a reduced pressure to obtain anintermediate reduced to an amino group (NH₂). The intermediate reactionproduct prepared thus was dissolved in hydrofuran (10 mL), and1,1′-carbodiimidazole (2 mmol) was added to the reaction product, andstirred at a room temperature for 1 hour. Then, excessive ammoniumhydroxide was added to the resulting reaction mixture, and the reactionmixture was stirred at a room temperature for additional 2 hours. Theresulting reaction mixture was diluted with water, and extracted severaltimes with ethyl acetate to obtain an organic phase. The preparedorganic phase was dried over magnesium sulfate, and concentrated under areduced pressure. The resulting pellet was purified with columnchromatography (hexane:ethyl acetate=1:1 to ethyl acetate) to obtain atitle compound.

¹H NMR (200 MHz, CDCl3) d: 2.78 (m, 1H), 2.91 (m, 2H), 3.02 (m, 2H),3.53 (m, 3H), 3.68 (m, 2H), 5.27 (br, 2H), 6.10 (t, 1H), 6.61 (d, 1H),6.73 (d, 1H), 6.91 (m, 1H), 7.00 (m, 1H), 7.32 (m, 6H)

Example 77 4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-1,4-dihydrobenzo[d][1,3]oxazin-2-one

Ethyl 2-nitro benzoylacetate (2.887 mmol) and phenylpiperazine (2.887mmol) were dissolved in toluene, and refluxed for 24 hours. Theresulting mixture was concentrated under a reduced pressure to obtain acrude compound. The prepared crude compound was dissolved in methanol,and cooled to 0° C., and sodium borohydride (2.887 mmol) was addedslowly to the resulting mixture. The mixture was stirred at a roomtemperature for 2 hours, and concentrated under a reduced pressure toremove solvents. Then, the resulting mixture was diluted with water, andextracted several times with ethyl acetate to obtain an organic phase.The prepared organic phase was dried over magnesium sulfate, filtered,and then concentrated under a reduced pressure. The resulting pellet waspurified with column chromatography (hexane:ethyl acetate=1:1) to obtaina compound. The prepared compound(3-(2-nitro-phenyl)-3-hydroxy-1-(4-phenyl-piperazin-1-yl)-propan-1-one,3 mmol) was dissolved in methanol, and subject to the hydrogenationreaction at the presence of a palladium catalyst to obtain an aminocompound with reduced nitro group. The prepared compound (1.21 mmol) wasdissolved in tetrahydrofuran (20 and triethylamine (3 mmol) was added tothe resulting reaction mixture. Phosgene (2.4 M toluene solution, 1.21mmol) was added slowly to the reaction mixture. In this case, atemperature of the reaction product was maintained in a temperaturerange of no more than 10° C. The reaction product was stirred at a roomtemperature for 16 hours, diluted with ammonium hydroxide, and thenextracted several times with ethyl acetate. The resulting organic phasewas dried over magnesium sulfate, and filtered, and the resultingfiltrate was concentrated under a reduced pressure, and re-crystallizedfrom ethyl acetate to prepare a final compound.

¹H NMR (200 MHz, CDCl3) d: 3.07 (m, 6H), 3.54 (m, 2H), 3.78 (m, 2H),6.01 (t, 1H), 6.88 (m, 4H), 7.05 (m, 1H), 7.26 (m, 4H), 8.46 (s, 1H)

Example 78 Carbamic acid3-[4-(3-hydroxy-4-methoxy)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and4-methoxy-3-hydroxy phenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 3.01 (m, 8H), 3.50 (m, 2H), 3.72 (m, 2H),3.84 (s, 3H), 4.77 (Br, 2H), 5.92 (s, 1H), 6.18 (t, 1H), 6.41 (dd, 1H),6.60 (d, 1H), 6.84 (d, 1H), 7.39 (m, 5H)

Example 79 (S)-carbamic acid3-[4-(4-fluoro)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and 4-fluorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.03 (m, 5H), 3.60 (m, 2H),3.76 (m, 2H), 4.73 (br, 2H), 6.16 (t, 1H), 6.95 (m, 4H), 7.38 (m, 5H

Example 80 (R)-carbamic acid3-[4-(4-methyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and4-methylphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.30 (s, 3H), 2.82 (dd, 1H), 3.05 (m, 5H),3.60 (m, 2H), 3.77 (m, 2H), 4.77 (br, 2H), 6.15 (t, 1H), 6.84 (d, 2H),7.10 (d, 2H), 7.38 (m, 5H)

Example 81 (S)-carbamic acid3-[4-(4-methyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and4-methylphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.30 (s, 3H), 2.82 (dd, 1H), 3.05 (m, 5H),3.60 (m, 2H), 3.77 (m, 2H), 4.77 (br, 2H), 6.15 (t, 1H), 6.84 (d, 2H),7.10 (d, 2H), 7.38 (m, 5H)

Example 82 (R)-carbamic acid3-[4-(2,4-difluoro)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and2,4-difluorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.95 (m, 6H), 3.61 (m, 2H), 3.80 (m, 2H),4.69 (br, 2H), 6.15 (t, 1H), 6.82 (m, 3H), 7.35 (m, 5H)

Example 83 (R)-carbamic acid3-[4-hydroxy-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and4-hydroxyphenylpiperazine.

¹H NMR (200 MHz, DMSO) d: 2.82 (m, 6H), 3.56 (m, 4H), 5.93 (t, 1H), 6.51(br, 2H), 6.67 (d, 2H), 6.78 (d, 2H), 7.37 (m, 5H), 8.88 (s, 1H)

Example 84 (S)-carbamic acid 3-[4-hydroxypiperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and4-hydroxyphenylpiperazine.

¹H NMR (200 MHz, DMSO) d: 2.82 (m, 6H), 3.56 (m, 4H), 5.93 (t, 1H), 6.51(br, 2H), 6.67 (d, 2H), 6.78 (d, 2H), 7.37 (m, 5H), 8.88 (s, 1H)

Example 85 (S)-carbamic acid3-[4-chloro-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

A title compound was synthesized in the same manner as in Example 61except for the use of (S)-3-hydroxy-3-phenylpropionic acid and4-chlorophenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.82 (dd, 1H), 3.07 (m, 5H), 3.58 (m, 2H),3.74 (m, 2H), 4.81 (br, 2H), 6.13 (t, 1H), 6.84 (d, 2H), 7.38 (m, 7H)

Example 86 Carbamic acid(R)-3-[4-(3-hydroxy-4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propylester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and3-methoxy-4-hydroxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.98 (m, 8H), 3.51 (m, 1H), 3.82 (m, 1H),3.88 (s, 3H), 4.81 (br, 2H), 5.40 (s, 1H), 6.01 (t, 1H), 6.4 (dd, 1H),6.92 (d, 1H), 7.39 (m, 5H)

Example 87 Carbamic acid(R)-3-[4-(3-methoxy-4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propylester

A title compound was synthesized in the same manner as in Example 61except for the use of (R)-3-hydroxy-3-phenylpropionic acid and3-hydroxy-4-methoxyphenylpiperazine.

¹H NMR (200 MHz, CDCl3) d: 2.99 (m, 8H), 3.47 (m, 1H), 3.50 (m, 1H),3.84 (s, 3H), 4.77 (br, 2H), 6.20 (t, 1H), 6.45 (dd, 1H), 6.59 (d, 1H),6.80 (d, 1H), 7.37 (m, 5H)

The compounds as listed above were tested for analgesic effects usingthe following animal models

2. Acetic Acid—Induced Writhing Test in Mouse

An acetic acid-induced writhing test is one of models for measuring ananalgesic effect of drugs. A test material dissolved in a suitablevehicle was orally administered to a male ICR mouse weighing 30 to 35 gat an amount of 10 mg/kg. After 1 hour of the oral administration, 10mg/ml of an aqueous 0.8% acetic acid solution was intraperitoneallyinjected into the male ICR mouse to induce the abdominal pain of themale ICR mouse. Right after the administration of acetic acid, the maleICR mouse was put into an empty cage, and the number of writhingbehaviors of the mice was counted for 10 minutes. The term “writhingrepresents a reflex action in which the mouse overtly extends itsabdomen by stretching its hind legs due to the abdominal pain. Theanalgesic effect of the test material is represented by the ‘suppressionof pain response’{[(Writhing number of vehicle-administeredgroup−Writhing number of Test material-administered group)/(Writhingnumber of Solvent-administered group)]×100%}. From these results, it wasobserved that the higher analgesic effect shows the higher suppressionof pain response.

3. Hot Plate Test in Mouse

A hot plate test is one of representative models for measuring ananalgesic effect of drugs. A test material dissolved in a suitablevehicle was orally administered to a male ICR mouse weighing 25 to 30 gat an amount of 30 mg/kg. After 1 hour of the oral administration, themouse was put on a hot plate (55° C.). A latency was recorded from thetime right after a mouse is put on a hot plate to the time whenavoidance responses (flinching, licking, jumping, etc.) to pain areobserved from forefeet or rear legs of the mouse. The analgesic effectof the test material is represented by the ‘Increase in latency ofavoidance response’{[(Latency of avoidance response to pain of Testmaterial-administered group−Latency of avoidance response to pain ofvehicle-administered group)/(Latency of avoidance response to pain ofSolvent-administered group)]×100%}. From these results, it was observedthat the higher analgesic effect shows the higher increase in latency ofavoidance response.

TABLE 1 Results on acetic acid - induced writhing test and hot platetest) in mouse Writhing Test Hot Plate Test Suppression of Increase inlatency of pain response avoidance response Compound (10 mg/kg, p.o) (30mg/kg, p.o) Example 1: carbamic acid 73.5% 17.0%3-[4-(4-fluoro-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 2: carbamic acid 54.6% 37.5%3-[4-(4-methoxy-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 3: carbamic acid 65.0% 38.5%3-[4-(3,4-dichloro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 4: carbamic acid 74.6% 34.1%3-oxo-1-phenyl-3-(4-p-tolyl-piperazin- 1-yl)-propyl ester Example 5:carbamic acid 79.7% 39.2% 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 6: carbamic acid 44.8% 11.0%1-(4-chloro-phenyl)-3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-propyl ester Example 7: carbamic acid40.9% 14.7% 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-1-(4-fluoro-phenyl)-3-oxo-propyl ester Example 8: carbamic acid30.1% 10.9% 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-p-tolyl-propyl ester Example 9: carbamic acid 33.1% 16.4%3-[4-(2,4-dimethoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 10: carbamic acid 26.0% 14.8%3-[4-(3,5-dichloro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 11: carbamic acid 5.5% 46.1%3-[4-(3,5-dimethoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 12: carbamic acid 37.0% 46.8%3-[4-(2,3-dichloro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 13: carbamic acid 64.0% 21.4%3-[4-(2,4-difluoro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 14: carbamic acid 64.0% 17.8%3-(4-benzo[1,3]dioxol-5-yl-piperazin- 1-yl)-3-oxo-1-phenyl-propyl esterExample 15: carbamic acid 35.1% 17.9%1-(4-methoxy-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 16: carbamic acid 37.3% 19.5%1-(4-chloro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 17: carbamic acid 25.3% 29.4%3-[4-(4-tert-butyl-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 18: carbamic acid 30.6% 26.4%3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 19: dimethyl-carbamic acid 34.2% 49.4%3-[4-(4-methoxy-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 20: carbamic acid 14.6% 45.4%3-[4-(3,4-dimethyl-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 21: carbamic acid 32.5% 51.4%3-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-oxo-1-phenyl-propyl ester Example 22: carbamic acid 29.4% 38.0%3-oxo-1-phenyl-3-(4-quinoxalin-2-yl-piperazin- 1-yl)-propyl esterExample 23: acetic acid 21.1% 29.4%4-[4-(3-carbamoyloxy-3-phenyl-propionyl)- piperazin-1-yl]-phenyl esterExample 24: carbamic acid 61.2% 28.1%3-oxo-1-phenyl-3-(4-pyridin-2-yl-piperazin- 1-yl)-propyl ester Example25: carbamic acid 59.3% 15.9%3-oxo-1-phenyl-3-(4-pyrimidin-2-yl-piperazin- 1-yl)-propyl ester Example26: carbamic acid 30.8% 20.6%3-[4-(3,5-dichloro-pyridin-2-yl)-piperazin- 1-yl]-3-oxo-1-phenyl-propylester Example 27: carbamic acid 29.1% 41.2%3-[4-(3-chloro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 28: carbamic acid55.6% 3.1% 3-oxo-1-phenyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl ester Example 29: carbamic acid 34.5%0.0% 3-[4-(2-fluoro-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 30: carbamic acid 9.2% 27.1%3-[4-(3-fluoro-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 31: carbamic acid 21.6% 20.1%3-oxo-3-(4-phenyl-piperazin-1-yl)-1-(4- trifluoromethyl-phenyl)-propylester Example 32: carbamic acid 6.0% 28.2%3-oxo-3-(4-phenyl-piperazin-1-yl)-1-p- tolyl-propyl ester Example 33:carbamic acid 74.5% 43.6% 3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 34: carbamic acid 38.4% 0.6%1-(4-nitro-phenyl)-3-oxo-3-(4-phenyl-piperazin- 1-yl)-propyl esterExample 35: carbamic acid 33.8% 32.8%3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-(4-trifluoromethyl-phenyl)- propyl ester; hydrochlorideExample 36: carbamic acid 42.0% 20.5%3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-1-(4-nitro-phenyl)-3-oxo-propyl ester; hydrochloride Example 37:carbamic acid 38.1% 10.0% 3-[4-(3,4-dichloro-benzyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 38: carbamic acid 66.1% 38.3%3-[4-(4-chloro-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 39: carbamic acid 23.2% 18.7%3-{4-[2-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-3-oxo-1-phenyl-propyl ester Example 40: carbamic acid 11.1% 27.8%4-[4-(3,4-dichloro-phenyl)-piperazin-1- yl]-4-oxo-1-phenyl-butyl esterExample 41: carbamic acid 31.2% 28.7%4-[4-(3,4-dimethoxy-phenyl)-piperazin- 1-yl]-4-oxo-1-phenyl-butyl esterExample 43: carbamic acid 46.0% 26.7%1-(2-chloro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 45: carbamic acid 19.0% 6.9%1-(3-trifluoro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 46: carbamic acid 71.3% 33.1%1-(3-bromo-phenyl)-3-oxo-3-(4-phenyl-piperazin- 1-yl)-propyl esterExample 47: carbamic acid 28.8% 27.2%2,2-difluoro-3-oxo-1-phenyl-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 49: carbamic 34.4% 20.6%acid-1-furan-3-yl-3-oxo-3-(4-phenyl-piperazin- 1-yl)-propyl esterExample 50: carbamic acid 15.0% 31.3%1-(3-methyl-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 51: carbamic acid 50.8% 29.2%1-(3-chloro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 52: carbamic 26.8% 20.5%acid-2-(4-phenyl-piperazine-1-carbonyl)-1,2,3,4-tetrahydro-naphthalene-1-yl ester Example 53: carbamic acid28.5% 10.6% 1-(3,4-dichloro-phenyl)-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester Example 55: carbamic acid 32.8% 13.9%1-(3,5-trifluoromethyl-phenyl)-3-oxo-3- (4-phenyl-piperazin-1-yl)-propylester Example 56: carbamic acid 23.3% 11.8%1-(2,4-dichloro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 57: carbamic acid 34.5% 11.2%1-(2,5-difluoro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 60: carbamic acid 28.0% 17.2%1-(3,4-difluoro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 61: (R)-carbamic acid 24.1% 38.8%3-[4-(4-chloro-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 62: (R)-carbamic acid 66.7% 13.8%3-[4-(4-fluoro-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 63: (R)-carbamic acid 59.8% 15.2%3-[4-(4-ethoxy-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 64: (S)-carbamic acid 41.1% 33.0%3-[4-(3,4-difluoro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 65: (S)-carbamic acid 32.4% 38.6%3-[4-(3,4-dimethoxy-phenyl)-piperazin- (30 mg/kg, p.o.)1-yl]-3-oxo-1-phenyl-propyl ester Example 66: (S)-carbamic acid 62.5%27.8% 3-[4-(3,4-dichloro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propylester Example 67: (R)-carbamic acid 45.1% 34.3%3-[4-(3,4-difluoro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 68: (R)-carbamic acid 51.0% 15.7%3-[4-(3,4-dichloro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 69: (S)-carbamic acid 11.4% 22.9%3-[4-(4-methoxy-phenyl)-piperazin-1-yl]- (30 mg/kg, p.o.)3-oxo-1-phenyl-propyl ester Example 70: (R)-carbamic acid 59.8% 30.6%3-[4-(4-methoxy-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 71: (R)-carbamic acid 46.5% 55.8%3-[4-(3,4-dimethoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 77: 26.4% 30.4% 4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-1,4-dihydro-benzo[d][1, 3]oxazin-2-one Example 79: (S)-carbamic acid40.7% 29.3% 3-[4-(4-fluoro)-piperazin-1-yl]-3-oxo- 1-phenyl-propyl esterExample 80: (R)-carbamic acid 36.3% 16.7%3-[4-(4-methyl)-piperazin-1-yl]-3-oxo- 1-phenyl-propyl ester Example 81:(S)-carbamic acid 20.1% 9.2% 3-[4-(4-methyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 82: (R)-carbamic acid 34.5% 65.7%3-[4-(2,4-difluoro)-piperazin-1-yl]-3- oxo-1-phenyl-propyl ester Example83: (R)-carbamic acid 44.5% 89.3%3-[4-hydroxy-piperazin-1-yl]-3-oxo-1-phenyl- propyl ester Example 84:(S)-carbamic acid 32.0% 13.5%3-[4-hydroxy-piperazin-1-yl]-3-oxo-1-phenyl- propyl ester Example 85:(S)-carbamic acid 52.0% 25.3%3-[4-chloro-piperazin-1-yl]-3-oxo-1-phenyl- propyl ester

Also, the compounds as listed above were tested for medicinal effects onthe anxiety and depression through the following animal experiments.

4. Elevated Plus Maze (EPM) Test in Mouse

Elevated plus maze (EPM) is one of representative models that examine ananti-anxiety activity of a test material. Equipment used for an EPM testhas a crossroad shape raised in a high position off the ground, and isconfigured in such a cliff shape that both sides of one road areprotected with high walls and the other road is free from the wall.Among them, the road in the cliff shape is referred to as an ‘open arm’,and the road protected by the walls is referred to as a ‘close arm’. Inthis case, a level of the anxiety of a mouse may be measured bydetermining in which arm the mouse stays longer. In general, the mousestays longer in the close arm than the open arm, but a mouse treatedwith a medicine showing an anti-anxiety effect stays relatively longerin the open arm. A test material dissolved in a suitable vehicle wasorally administered to a male ICR mouse weighing 20 to 25 g at an amountof 10 mg/kg. After 1 hour of the oral administration, the mouse was puton the center of an EPM equipment to measure how long the mouse stays inthe open arm within a time range of 5 minutes. The anti-anxiety effectof the test material is represented by the ‘Change index in Open-ArmTime’[(open arm duration in test material-administered group−open armduration in vehicle-administered group)/(open arm duration in vehicleadministered group)]×100%). From these results, it was observed that theincrease of the open-arm time shows the increase in the anti-anxietyeffect.

5. Test on Head Twitch Potentiation Induced by 5-HTP (5-HTP PotentiationTest) in Mouse

When 5-hydroxy-L-tryptophan (5-HTP) is administered into a mouse, a headtwitch phenomenon is observed since serotonin is increasingly secretedin the mouse. In this case, when the mouse is treated with amonoamineoxidase-A (MAO-A) suppressor that further potentiates serotoninactivity, or an antidepressant agent such as a selective serotoninreuptake inhibitor (SSRI), the head twitch count of a mouse issignificantly increased. By using this principle, it is possible tosearch an effect of the representative antidepressant agent. A testmaterial dissolved in a suitable vehicle was orally administered to amale ICR mouse weighing 20 to 25 g at an amount of 30 mg/kg. After 30minutes of the oral administration, 5-HTP (80 mg/kg) and 5-HTPperipheral decarbozylase inhibitor ‘Carbidopa (25 mg/kg) wereintraperitoneally administered to the mouse. After 30 minutes of theintraperitoneal administration, the mouse was put into an observationcage, and head twitches of the mouse were counted for 2 minutes. Theanti-depression effect of the test material is represented by the‘Increase rate in Head Twitch No.’{[(Head Twitch No. of Testmaterial-administered group−Head Twitch No. of vehicle-administeredgroup)/(Head Twitch No. of vehicle-administered group)]×100%}. Fromthese results, it was observed that the higher anti-depression effect isrelated to the ‘higher increase of Head Twitch numbers.’ Also, when the‘increase rate in Head Twitch numbers’ is measured to be negative, itindicates that the corresponding compound serves as an antagonist to a5-HT2A receptor (Darmani NA, J. Neural Transm., 1998; 105(6-7):635-643).In addition to the selective serotonin reuptake inhibitor (SSRI) thathas been widely used as an antidepressant agent in the clinical fields,it was tested that 5-HT2A antagonists such as nefazodone and trazodonealso have an antidepressant effect.

TABLE 2 Results on EPM (Elevated Plus Maze) test and 5- HTP - inducedhead twitch response test in mouse Elevated Plus Maze 5-HTP PotentiationChange index in Increase rate in Head Open-Arm Time Twitch No. compound(10 mg/kg, p.o) (30 mg/kg, p.o) Example 1: carbamic acid 25.6% −65.7%3-[4-(4-fluoro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 3: carbamic acid  9.7% 54.5%3-[4-(3,4-dichloro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 4: carbamic acid 41.1% −7.1%3-oxo-1-phenyl-3-(4-p-tolyl-piperazin- 1-yl)-propyl ester Example 10:carbamic acid 27.3% 85.7% 3-[4-(3,5-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 11: carbamic acid 19.8% 31.3%3-[4-(3,5-dimethoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 12: carbamic acid 41.1% 10.0%3-[4-(2,3-dichloro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 13: carbamic acid 12.6% −60.0%3-[4-(2,4-difluoro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 16: carbamic acid  1.3% 140.0%1-(4-chloro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 17: carbamic acid 34.0% 10.0%3-[4-(4-tert-butyl-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 18: carbamic acid 16.1% −23.4%3-[4-(4-hydroxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 19: dimethyl-carbamic acid  0.0% 60.0%3-[4-(4-methoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 20: carbamic acid 45.4% −6.3%3-[4-(3,4-dimethyl-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 21: carbamic acid 67.5% −7.0%3-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-oxo-1-phenyl-propyl ester Example 22: carbamic acid−21.2%  3.9% 3-oxo-1-phenyl-3-(4-quinoxalin-2-yl- piperazin-1-yl)-propylester Example 23: acetic acid −25.1%  100.0%4-[4-(3-carbamoyloxy-3-phenyl-propionyl)- piperazin-1-yl]-phenyl esterExample 27: carbamic acid 66.7% −78.1%3-[4-(3-chloro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl- propyl ester Example 28: carbamic acid−1.4% −12.5% 3-oxo-1-phenyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl ester Example 29: carbamic acid 92.3%14.3% 3-[4-(2-fluoro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propylester Example 30: carbamic acid 102.0%  40.0%3-[4-(3-fluoro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 31: carbamic acid 35.6% 10.0% 3-oxo-3-(4-phenyl-piperazin-1-yl)-1-(4-trifluoromethyl-phenyl)-propyl ester Example 32: carbamic acid 9.5% −40.0% 3-oxo-3-(4-phenyl-piperazin-1-yl)- 1-p-tolyl-propyl esterExample 34: carbamic acid  6.5% 2.9%1-(4-nitro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 35: carbamic acid 44.0% 64.3%3-[4-(3,4-dimethoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-(4-trifluoromethyl-phenyl)-propyl ester; hydrochloride Example 36: carbamic acid 35.3%93.8% 3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-1-(4-nitro-phenyl)-3-oxo- propyl ester; hydrochloride Example 37:carbamic acid 98.8% 166.7% 3-[4-(3,4-dichloro-benzyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 39: carbamic acid 57.8% 319.0%3-{4-[2-(3,4-dichloro-phenyl)-ethyl]- piperazin-1-yl}-3-oxo-1-phenyl-propyl ester Example 40: carbamic acid 68.8% 311.1%4-[4-(3,4-dichloro-phenyl)-piperazin- 1-yl]-4-oxo-1-phenyl-butyl esterExample 42: carbamic acid 27.3% 33.3%1-(2-nitro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 43: carbamic acid 19.7% 211.1%1-(2-chloro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 45: carbamic acid 74.5% 166.7%1-(3-trifluoro-phenyl)-3-oxo-3-(4- phenyl-piperazin-1-yl)-propyl esterExample 46: carbamic acid  5.7% 40.3%1-(3-bromo-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 47: carbamic acid 21.4% 22.5%2,2-difluoro-3-oxo-1-phenyl-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 49: carbamic 48.9% −20.0% acid-1-furan-3-yl-3-oxo-3-(4-phenyl-piperazin-1-yl)-propyl ester Example 50: carbamic acid 65.4% −21.3%1-(3-methyl-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 51: carbamic acid −0.7% 40.3%1-(3-chloro-phenyl)-3-oxo-3-(4-phenyl- piperazin-1-yl)-propyl esterExample 52: carbamic 14.6% 40.0%acid-2-(4-phenyl-piperazine-1-carbonyl)- 1,2,3,4-tetrahydro-naphthalene-1-yl ester Example 53: carbamic acid −17.7%  50.0%1-(3,4-dichloro-phenyl)-3-oxo-3-(4- phenyl-piperazin-1-yl)-propyl esterExample 55: carbamic acid 13.8% 22.5%1-(3,5-trifluoromethyl-phenyl)-3-oxo- 3-(4-phenyl-piperazin-1-yl)-propylester Example 56: carbamic acid 23.9% 40.0%1-(2,4-dichloro-phenyl)-3-oxo-3-(4- phenyl-piperazin-1-yl)-propyl esterExample 57: carbamic acid 88.8% 27.9%1-(2,5-difluoro-phenyl)-3-oxo-3-(4- phenyl-piperazin-1-yl)-propyl esterExample 60: carbamic acid 21.3% −23.5%1-(3,4-difluoro-phenyl)-3-oxo-3-(4- phenyl-piperazin-1-yl)-propyl esterExample 61: (R)-carbamic acid −27.4%  27.3%3-[4-(4-chloro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 62: (R)-carbamic acid  2.7% 0.8%3-[4-(4-fluoro-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 63: (R)-carbamic acid 25.0% 19.5%3-[4-(4-ethoxy-phenyl)-piperazin-1- yl]-3-oxo-1-phenyl-propyl esterExample 64: (S)-carbamic acid 125.2%  133.8%3-[4-(3,4-difluoro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 65: (S)-carbamic acid 74.7% 91.6%3-[4-(3,4-dimethoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 66: (S)-carbamic acid 50.6% −39.5%3-[4-(3,4-dichloro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 67: (R)-carbamic acid 34.3% 58.8%3-[4-(3,4-difluoro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 68: (R)-carbamic acid  1.5% −28.6%3-[4-(3,4-dichloro-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 69: (S)-carbamic acid 57.3% −14.3%3-[4-(4-methoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 70:: (R)-carbamic acid  109% 87.9%3-[4-methoxy-phenyl)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl esterExample 71: (R)-carbamic acid 125.4%  126.7%3-[4-(3,4-dimethoxy-phenyl)-piperazin- 1-yl]-3-oxo-1-phenyl-propyl esterExample 77:  4.9% 25.0% 4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-1,4-dihydro-benzo[d][1, 3]oxazin-2-one Example 79: (S)-carbamicacid −5.1% −30.0% 3-[4-(4-fluoro)-piperazin-1-yl]-3- oxo-1-phenyl-propylester Example 80: (R)-carbamic acid 41.2% 12.5%3-[4-(4-methyl)-piperazin-1-yl]-3- oxo-1-phenyl-propyl ester Example 81:(S)-carbamic acid 23.0% −21.4% 3-[4-(4-methyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 82: (R)-carbamic acid 62.6% −20.0%3-[4-(2,4-difluoro)-piperazin-1-yl]- 3-oxo-1-phenyl-propyl ester Example83: (R)-carbamic acid 52.7% 40.9% 3-[4-hydroxy-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester Example 84: (S)-carbamic acid 65.6% −37.5%3-[4-hydroxy-piperazin-1-yl]-3-oxo- 1-phenyl-propyl ester Example 85:(S)-carbamic acid 37.0% 222.2% 3-[4-chloro-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester

For the use in treating various diseases such as a wide range of pains(including acute pain, chronic pain, neuropathic pain, post-surgeryneuropathic pain, diabetic neuropathic pain, postherpetic neuralgia,inflammatory pain, joint pain, and migraine headache and the like),anxiety and depression, the compound of the present invention isadministered to patient, alone or in combinations with pharmaceuticallyavailable carriers. An exact dose of the administered compound may bedetermined according to the conditions of patients, the severity ofpatient status and the activity of the compound. Under the specificcircumstances, the optimum dose of the administered compound shouldessentially be determined in a clinical manner, but be present withinthe scope of the present invention.

For the use of the compound according to the present invention, thecompound is preferably administered orally since the compound is easilyabsorbed orally, but the present invention is not particularly limitedthereto. For the oral administration, the compound according to thepresent invention is preferably used in combinations with apharmaceutical carrier. A dose ratio of the carrier to the inventivecompound is limited to allow the compound to take an effect on patients,and may be widely varied, depending on whether the composition is filledinto a capsule, or formulated into a tablet. In the case of the tablet,edible and pharmaceutical carriers or mixtures thereof may be usedherein. Examples of the suitable carriers includes, but are notparticularly limited to, lactose, dibasic calcium phosphate and/or cornstarch, and mixtures thereof, etc. Other pharmaceutically availablecompounds may be further added, including a lubricant such as magnesiumstearate.

1. A carbamoyloxy arylalkanoyl arylpiperazine derivative compound havingabundant racemic or enantiomeric characteristics, represented by thefollowing Formula 1, and pharmaceutically available salts or hydratesthereof:

wherein,

may selectively form a cyclic ring; R₁ and R₂ are each independentlyselected from the group consisting of hydrogen, straight or branchedalkyl having carbon atoms of 1 to 6, and phenethyl, or R₁ and R₂ may betaken together to form a 5-membered or 6-membered heterocyclic ring orR₁ or R₂ may be taken together with Ar₁ to form a bicyclic ring; Ar₁ isselected from the group consisting of furanyl, thionyl,methylene-dioxyphenyl, and phenyl that may be substituted by at leastone identical or different substituent selected from the groupconsisting of hydrogen, straight or branched alkyl having carbon atomsof 1 to 6, halogen such as F, Cl and Br, straight or branched alkoxyhaving carbon atoms of 1 to 6, nitro, and trifluoromethyl; Z is hydrogenor fluorine, or may be taken together with Ar₁ to form a bicyclic ring;Ar₂ is selected from the group consisting of phenyl,methylenedioxyphenyl, pyridine, pyrimidine, naphthyl, bis(fluorophenyl)methyl and quinoxaline, all of which may be substituted by atleast one identical or different substituent selected from the groupconsisting of hydrogen, straight or branched alkyl having carbon atomsof 1 to 6, hydroxy, halogen, straight or branched alkoxy having carbonatoms of 1 to 6, nitro, acetyl, t-butylacetyl, trifluoromethyl, amino,and acetate; n is integer of 1 or 2; and m is integer ranging from 0 to2.
 2. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound is represented by the followingFormula 2:

wherein, X₁ is at least one selected from the group consisting ofhydrogen, straight or branched alkyl having carbon atoms of 1 to 6,halogens such as F, Cl and Br, straight or branched alkoxy having carbonatoms of 1 to 6, nitro, and trifluoromethyl, provided that, when X₁ isat least two selected from the groups, the two substituents may beidentical to, or different from each other.
 3. The compound and thepharmaceutically available salts or hydrates thereof of claim 2, whereinthe compound is represented by the following Formula 3:

wherein, X₁ is hydrogen; and X₂ is at least one selected from the groupconsisting of hydrogen, straight or branched alkyl having carbon atomsof 1 to 6, hydroxy, halogen, straight or branched alkoxy having carbonatoms of 1 to 6, nitro, t-butylacetyl, trifluoromethyl, and amino,provided that, when X₂ is at least two selected from the groups, the twosubstituents may be identical to, or different from each other.
 4. Thecompound and the pharmaceutically available salts or hydrates thereof ofclaim 1, wherein the compound comprises carbamic acid3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester. 5.The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises (R)-carbamic acid3-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester. 6.The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises (R)-carbamic acid3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester. 7.The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises carbamic acid3-[4-(3,4-dichloro-benzyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.8. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises carbamic acid4-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-4-oxo-1-phenyl-butyl ester.9. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises carbamic acid3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.10. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises (S)-carbamic acid3-[4-(3,4-dichloro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.11. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises carbamic acid3-[4-(4-methyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester. 12.The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises (S)-carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.13. The compound and the pharmaceutically available salts or hydratesthereof of claim, 1, wherein the compound comprises (R)-carbamic acid3-[4-(3,4-dimethoxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.14. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises carbamic acid3-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.15. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises (S)-carbamic acid3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.16. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises (R)-carbamic acid3-[4-(3,4-difluoro-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.17. The compound and the pharmaceutically available salts or hydratesthereof of claim 1, wherein the compound comprises carbamic acid3-[4-(3-chloro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propylester.
 18. The compound and the pharmaceutically available salts orhydrates thereof of claim 1, wherein the compound comprises carbamicacid3-oxo-1-phenyl-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propylester.
 19. The compound and the pharmaceutically available salts orhydrates thereof of claim 1, wherein the compound comprises (R)-carbamicacid 3-[4-hydroxy-piperazin-1-yl]-3-oxo-1-phen yl-propyl ester.
 20. Thecompound and the pharmaceutically available salts or hydrates thereof ofclaim 1, wherein the compound comprises (S)-carbamic acid3-[4-chloro-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester.
 21. Thecompound and the pharmaceutically available salts or hydrates thereof ofclaims 1 to 20, wherein the salts of the compound comprisemethanesulfonate salt and hydrochloride.
 22. A pharmaceuticalcomposition for treating anxiety or depression, comprising an effectiveamount of the compound having abundant racemic or enantiomericcharacteristics as defined in any one of claims 1 to
 20. 23. Apharmaceutical composition for treating pain, comprising an effectiveamount of the compound having abundant racemic or enantiomericcharacteristics as defined in any one of claims 1 to
 20. 24. Thepharmaceutical composition of claim 23, wherein the pain comprises acutepain; chronic pain, neuropathic pain, post-surgery neuropathic pain,diabetic pain, postherpetic neuralgia, inflammatory pain, joint pain,and migraine headache.
 25. A method for treating pain, anxiety ordepression in mammals by administering to the mammals in need oftreatment thereof an effective amount of the compound having abundantracemic or enantiomeric characteristics as defined in any one of claims1 to
 20. 26. The method of claim 25, wherein the effective amount of thecompound is administered in a unit dose comprising 20 to 500 mg of thetotal active components, and in a daily dose of 10 to 7000 mg.